Understanding the origins of protein conformational behavior is a longstanding goal in biomolecular science because protein function often depends upon proper folding, and aberrant protein behavior can lead to human disease. Although much progress has been made, many important questions remain unanswered. Our program focuses on problems that benefit from, and in some cases require, the application of unconventional chemical strategies (involving synthesis of unnatural subunits and polypeptides) in concert with traditional tools of biophysics. One long-term effort involves the development of molecules that fold autonomously to parallel -sheet secondary structure in aqueous solution, which represent unique tools for assessing structure-stability relationships for parallel -sheet secondary structure in the absence of a specific tertiary context. Proposed studies include a novel initiativ to add a third dimension to autonomously folding -sheets by creating mini-solenoids, which would represent small segments of amyloid-like structure. These molecules are intended to enable us to probe amyloid packing phenomena via powerful solution-phase analytical methods. A second long-term effort involves a focus on coiled-coil interactions. The proposed research includes an effort to apply basic insights on coiled-coil pairing preferences to develop inhibitors of a protein assembly that underlies Streptococcal toxic shock. A third component of the proposed research involves application of racemic and quasi-racemic crystallography to acquire high-resolution insight on structural phenomena that are otherwise difficult or impossible to study. We propose to use racemic crystallography to characterize homo- and heterotypic associations involving transmembrane helix segments of cell-surface receptors. Such information is currently inaccessible, which hinders our understanding of signal transduction mechanisms. We propose to use quasi-racemic crystallography to identify guidelines for mimicking protein structural motifs with backbones that contain unnatural subunits. These studies could lay a foundation for rational engineering of novel biomedical agents.